The 13-cis-retinoic acid characterized by the following formula: ##STR1## is an active principle that finds widespread practical application in various treatments and is used in particular for the treatment of acne. In "Carotenoids and Related Compounds. Part XVIII. Synthesis of cis and Di-cis-Polyenes by Reactions of Wittig Type", Paddenten G., Weedon B. C. L., J. Chem. Soc. (C) 1968, pages 1984-1997, a process is described for preparing this product, which comprises a Wittig condensation at ambient temperature in ethereal solvent in the presence of sodium methoxide of the halide of 3-methyl-5-(2,6,6-trimethyl-1-cyclohexene-1-yl-2,4-pentadienyl!-triphenyl -phosphonium of formula (II) ##STR2## where X is a halogen atom, with 5-hydroxyl-4-methyl-2(5-H)-furanone of formula (III) ##STR3## This process, however, presents the disadvantage that the desired product is obtained mixed with the following isomers: 11-cis-, 13-cis-retinoic acid of formula (IV) ##STR4## and 11-trans-,13-trans-retinoic acid (i.e., the acid of vitamin A), of formula (V) ##STR5## The product (I) obtained in a minority amount compared to the isomer (IV) and in amounts more or less comparable to those of the isomer (V), must then be separated from the mixture with conventional methods for silica chromatography by means of fractional crystallization, these being treatments which further reduce the yields.
The patent EP 0111325 describes a process for preparation of 13-cis-retinoic acid, characterized by the fact that the Wittig condensation between product (II) and product (III) occurs at low temperatures of between -10.degree. C. and -50.degree. C. in alcoholic solvent and in the presence of bases consisting of alkaline metal hydroxides, such as potassium hydroxide.
In this way, a conversion is obtained of over 90% calculated with respect to the starting product (III); the reaction product consists of a mixture containing between 10% and 30% of isomer (I) and between 70% and 90% of isomer (IV). The mixture as such, or the isomer (IV) alone previously separated from the aforesaid mixture, undergoes a process of isomerization in the presence of rhodium-based or palladium-based catalysts that are able to convert the product (IV) into 13-cis-retinoic acid.
Although this process enables 13-cis-retinoic acid to be obtained in higher yields than those obtained with the process described in the previous document, it presents the drawback that the isomerization of 11-cis,13-cis-retinoic acid of formula (IV) occurs with catalysts containing transition metals, such as rhodium and palladium, that are extremely costly. In addition, it is very difficult to recover the 13-cis-retinoic acid from the raw reaction product containing the aforesaid catalysts with the chemical purity required by current manufacturing standards.
The patent DE 4313089 describes a process to prepare 13-cis-retinoic acid in which the reaction between 5-hydroxyl-4-methyl-furanone (III) with the salt of 3-methyl-5-(2,6,6-trimethy-1-1-cyclohexene-1-yl)-2,4-pentadienyltriaryl-p hosphonium (II) is carried out in the presence of lithium hydroxide and dimethylformamide at temperatures of between 10.degree. C. and -9.degree. C. to obtain a mixture of lithium salts of 13-cis-retinoic acid and of 11-cis, 13-cis-retinoic acid, which are subsequently solubilized in water and converted into their respective acids by addition of sulphuric acid. The residue is recovered which consists of a mixture of the two acids and which is then solubilized in alcoholic solvent, and subsequently undergoes photochemical isomerization to obtain 13-cis-retinoic acid.
Even though this method represents a considerable improvement over the previous process in that the isomerization process does not require the use of the aforesaid catalysts, it presents a series of drawbacks in that photochemical isomerization must be carried out on the mixture of the isomers coming from the Wittig condensation, previously isolated from the reaction solvents. The aforesaid retinoic acids are moreover not very soluble in the reaction solvents compatible with photochemical isomerization. In fact, photochemical isomerization must be carried out only on solutions of the aforesaid solvents containing the mixture of acids in concentrations of less than 10%. This type of photochemical isomerization, if applied on an industrial scale, requires considerable quantities of solvents, which is disadvantageous from the economic standpoint of the process, as well as from the standpoint of the safety of operators carrying out this process. In addition to this, the use of organic solvent for this type of reaction entails particular equipment and costly fire-prevention and explosion-prevention systems. Furthermore, the mixture of acids is rather unstable in organic solvents.
For these reasons, the need has been felt for having available a process for the production of 13-cis-retinoic acid that should not present the drawbacks of the processes known in the present state of the art.